Failure of osseointegration (direct anchorage of an implant by bone formation at the bone-implant surface) and implant infection are the two main causes of implant failure and loosening. There is an urgent need for orthopedic implants that both promote rapid osseointegration and prevent bacterial colonization, particularly when placed in bone compromised by disease or the physiology of the patients. The goal of this study is to develop a bactericidal ?bone-like? nanofiber (NF) coating to enhance osseointegration while preventing implant infection. To imitate the architecture of the natural bone matrix, we developed coaxial electrospun NFs composed of poly (lactide-co-glycolide) (PLGA) and polyvinyl alcohol (PVA) polymers arranged in a core- sheath configuration. PLGA is a FDA-approved co-polymer with long clinical experience as a carrier for sustained drug release. Type I collagen (Col) was embedded in the PLGA to form a bioactive PLGACol sheath fiber. PVA has a good fiber-forming capability and will be used to encapsulate nanoscale hydroxyapatite (HA) to form a hydrophilic PVAHA core fiber. The PLGACol/PVAHA NFs are biocompatible and biodegradable with appropriate fiber diameter, pore size and mechanical strength, leading to enhanced cell adhesion, proliferation and differentiation of bone marrow stromal cells (BMSCs). In the proposed study, we will embed erythromycin (EM, bactericidal and anti-osteoclastic) into PLGACol/PVAHA NFs. We hypothesize that NFs will mimic the biological, structural and mechanical behaviors of natural bone, and enhance the adhesion, growth and differentiation of BMSCs. We propose that the embedding of EM in the PLGACol/PVAHA NFs will inhibit bacterial colonization and promote implant osseointegration because of its stimulatory activity of bone healing. We will test our hypothesis by pursuing three Aims: Aim 1: Develop an optimal PLGACol/PVAHA NF formulation for titanium (Ti) implant coating: (a) Define an optimal NF formulation based on the cellular response (viability, proliferation and osteogenic differentiation of rat BMSCs, and (b) Further optimize the bonding strength of NF coating to the Ti implant in an ex vivo porcine bone implantation model; Aim 2: Characterize the effects of EM doping of PLGACol/PVAHA NFs on the cellular response, bacterial growth and biofilm formation in vitro. We propose that EM doping will change the physiochemical nature of NFs (morphology, surface topology, degradation, mechanical strength and EM release dynamics, Aim 2a), which will impact on the cellular response (viability, proliferation and osteogenic differentiation of rat BMSCs, Aim 2b), and bacterial growth and biofilm formation (adhesion, viability and biofilm formation of Staphylococcus aureus, S. aureus, Aim 2c), and Aim 3: Determine the effects of EM doping of PLGACol/PVAHANFs on infection inhibition and osseointegration in a rat S. aureus- infected tibia implantation model. We will determine whether the EM-NF coating is sufficient to inhibit implant infection (bacterial culture, biofilm formation) and enhance osseointegration (pullout test, bone histomorphometry, and micro computed tomography, ?CT). We expect that a sustained release of EM from NF coating will inhibit implant infection and further promote osseointegration due to its proven osteogenic and bactericidal activities. The proposed work is innovative, because it capitalizes on a new strategy of implant surface fabrication by providing a ?bone-like? nanoscale topology and a reservoir of controllable sustained drug release. It is our expectation that the resultant approach will provide solid evidence favoring the advantages of the proposed NF coated medical devices over those currently available. These results will be significant, because they are expected to improve the success of total joint replacement and increase implant longevity. It should not appreciably increase the cost of the implant. This will improve the quality of life for these patients and provide a significant healthcare savings.